Systems and methods for intravascular cooling

ABSTRACT

Methods and systems for infusing a cooled infusate to a target location in a patient are described. A temperature of the blood and infusate admixture upstream of the catheter as well as at other locations along the catheter may be monitored and a feedback system utilized to control the volume, temperature, and/or infusion rate of the infusate so as to achieve a predetermined temperature at the target location. Control may also be based on the patient&#39;s native vessel flow rate. The system may monitor or calculate hematocrit upstream of the catheter and adjust infusion so as to provide sufficient oxygenation of the blood and infusate admixture. The system may also monitor reflux of the infusate past a distal end of the catheter and reduce infusion upon the detection of reflux.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of and claims the benefit ofand priority to International Patent Application Serial No.PCT/US2006/045374, filed on Nov. 22, 2006, which claims the benefit ofand priority to U.S. Provisional Patent Application Ser. No. 60/753,433,filed on Dec. 22, 2005, both of which are expressly incorporated hereinin their entireties by reference thereto.

FIELD OF THE INVENTION

The present invention is directed to systems and methods forintravascular cooling. More particularly, the present invention relatesto intravascular cooling catheter systems and methods useful for coolingan organ such as the brain or other tissue.

BACKGROUND INFORMATION

Organs of the human body, such as the brain, kidney, and heart, aremaintained at a constant temperature of approximately 37° C. Cooling isbelieved to be the most effective ischemia mitigator. More particularly,cooling of organs below 35° C. is believed to provide cellularprotection from anoxic damage caused by a disruption of blood supply orby trauma. Also, cooling can reduce internal or external swellingassociated with traumatic injuries.

Hypothermia is currently a useful medical tool and is sometimesperformed to protect the brain or other organs from injury. Cooling ofthe brain is generally accomplished through whole body cooling to createa condition of total body hypothermia in the range of from 20° to 30° C.This cooling is accomplished by immersing a patient in ice, by usingcooling blankets, or by cooling the blood flowing externally through acardiopulmonary bypass machine. U.S. Pat. No. 3,425,419 (“Dato”) andU.S. Pat. No. 5,486,208 (“Ginsburg”) describe catheters for cooling theblood by circulating a cold fluid to create total body hypothermia. Thesystems of Dato and Ginsburg, however, are believed to be unsuitable forselective organ hypothermia because they do not provide for selectiveorgan cooling. Hypothermia is achieved by circulating a cold fluidwithin each of the Dato and Ginsburg catheters, which are designed to beused in the great vessels like the inferior vena cava. Even if thecatheters are placed in a selective vessel supplying an organ, therewould be no manner of detecting when a desired temperature has beenreached because there is no feedback system regarding the effect of thecatheter on the selected organ temperature.

Use of total body hypothermia to provide organ protection is believed tohave a number of drawbacks. First, it may create cardiovascularproblems, such as cardiac arrhythmias, reduced cardiac output, andincreased systemic vascular resistance, which side effects can result inorgan damage. These side effects are believed to be caused reflexivelyin response to the reduction in core body temperature. Second, totalbody hypothermia is difficult to administer. Immersing a patient in icewater has its associated problems. Placement on cardiopulmonary bypassrequires surgical intervention and specialists to operate the machine,and this procedure is associated with a number of complications,including bleeding and volume overload. And third, the time required toreduce the body temperature and the organ temperature is prolonged.Minimizing the time between injury and the onset of cooling is believedto produce better clinical outcomes.

Some physicians are believed to have immersed a patient's head in ice toprovide brain cooling. Also, there are cooling helmets, or head gear, toperform a similar function. This approach suffers from the problems ofslow cool down and poor temperature control due to the temperaturegradient that must be established externally to internally. It isbelieved that complications associated with total body cooling, such asarrhythmia and decreased cardiac output, can be caused by cooling of theface and head only.

Selective organ hypothermia has been studied. See, for example, A. E.Schwartz et al., “Isolated Cerebral Hypothermia by Single Carotid Arteryperfusion of Extracorporeally Cooled Blood in Baboons”, Neurosurgery,Vol. 39, No. 3, September 1996, pp. 577-582, and A. E. Schwartz et al.,“Selective Cerebral Hypothermia by Means of Transfemoral InternalCarotid Artery Catheterization,” Radiology, Vol. 201, No. 2, November1996, pp. 571-572. Utilizing baboons, blood is circulated and cooledexternally from the body via the femoral artery and returned to the bodythrough the carotid artery. These studies are believed to show that thebrain could be selectively cooled to temperatures of 20° C. withoutreducing the temperature of the entire body. Subsequently,cardiovascular complications associated with total body hypothermia arenot believed to have occurred.

Selective organ hypothermia is believed to have been attempted byperfusing an organ with a cold solution, such as saline or aperfluorocarbon. A type of selective organ hypothermia referred to ascardioplegia is performed to protect the heart during heart surgery.Cardioplegia has a number of drawbacks, including limited time ofadministration due to excessive volume accumulation, cost andinconvenience of maintaining the perfusate, lack of effectiveness due totemperature dilution from the blood, lack of a method to monitorhemodilation, and the decrease in the hematocrit of the blood supply toselected organs. Temperature dilution by the blood is a particularproblem in high blood flow organs such as the brain. For cardioplegia,the blood flow to the heart is minimized; therefore, temperaturedilution is minimized.

A conventional cooling catheter is believed to employ a feedback systemto control the temperature of the cooled infusate. There is believed tobe a need, however, for an intravascular system and method for corporealcooling which provides for a more accurate and effective control of thevolume and temperature of the cooled infusate and which is safer for thepatient.

SUMMARY

According to an exemplary embodiment of the present invention, a devicemay include an insertion device, such as a catheter, adapted tofluidicly communicate with a source of an infusate and a controller. Thecontroller may be adapted to control at least one of (a) a temperatureof the infusate, (b) an infusion rate of the infusate through theinsertion device, and (c) a volume of the infusate passing through theinsertion device, in accordance with a temperature of a blood andinfusate mixture downstream relative to an infusate exit location of theinsertion device while the insertion device is placed in a blood vesselof a patient for infusion of the infusate, and in accordance with atleast one of (a) a temperature of the infusate at or adjacent the exitlocation, (b) a temperature upstream and adjacent the exit location, and(c) a core body temperature of the patient. The infusate flows throughthe insertion device and, assuming no reflux or a substantial absence ofreflux, through the blood vessel in a downstream direction.

Upstream refers to a direction opposite the direction of flow ofinfusate through the insertion device, when the insertion device ispassed into a blood vessel in the direction of blood flow, and refers tothe same direction in which the infusate flows through the insertiondevice, when the insertion device is passed into a blood vessel in adirection opposite the blood flow. For example, in the context ofcatheter used to cool the brain and inserted through a groin vascularaccess site in the common femoral artery and navigated to one of thecommon carotid arteries, as detailed below, the term upstream hereinrefers to the direction towards the aortic arch and the term downstreamherein refers to the direction towards the internal carotid artery.Further, in the context of a catheter used to cool a patient's leg andinserted through a groin vascular access site in the common femoralartery and navigated into the common iliac artery, as detailed below,the term upstream herein refers to the direction towards the aorta andthe term downstream herein refers to the direction towards the commonfemoral artery.

The device may include a plurality of temperature sensors, wherein thecontroller is adapted to receive signals from the temperature sensors.At least one of the temperature sensors may be positioned downstreamrelative to the infusate exit location and may be adapted to measure atemperature of the infusate and blood mixture. At least another one ofthe temperature sensors may be adapted to measure at least one of (a) atemperature of the infusate at or adjacent the exit location, (b) atemperature upstream and adjacent the exit location, and (c) a core bodytemperature of the patient.

The temperature sensors may be at least one of (a) connected to theinsertion device, (b) connected to a second device, and (c) connected toboth the insertion device and the second device. The second device maybe at least one of (a) arranged adjacent to the insertion device, (b)connected to the insertion device, and (b) arranged so as to extendthrough the insertion device.

The controller may be adapted to control at least one of (a) thetemperature of the infusate, (b) the infusion rate of the infusatethrough the insertion device, and (c) the volume of the infusate passingthrough the insertion device to at least one of detect and control atemperature of the infusate and blood mixture. The flow of infusate maybe maintained, e.g., for a predetermined period of time and/or untilreflux is detected.

The insertion device may be in fluid communication with the source ofinfusate.

The device may further include a pump or valve controlled by thecontroller and adapted to provide or direct infusate from the infusatesource through the insertion device.

The device may further include a first valve, adapted to control flow ofinfusate from a first infusate reservoir through the insertion device,and a second valve, adapted to control flow of infusate from a secondinfusate reservoir through the insertion device. The temperatures of thefirst and second infusate reservoirs may be different and the device maybe configured to control the temperature of the infusate flowing throughthe insertion device via coordinated control of both the first valve andthe second valve.

The device may further include a heat exchanger controlled by thecontroller and adapted to control the temperature of the infusate.

The device may further include a guide catheter adapted to be disposedabout the catheter.

The device may further include an insulator disposed about the insertiondevice.

The guide catheter may be configured to enlarge from a first low profileto a second larger profile so as to at least one of create and increasein size an insulating annular space between the catheter and the guidecatheter.

The temperature sensor adapted to measure temperature upstream andadjacent the exit location may be located, for example, about 0.2 cm toabout 5 cm upstream the exit location.

The controller may be adapted to control at least one of (a) an infusionrate of the infusate through the insertion device and (b) a volume ofinfusate passing through the insertion device in accordance with anadmixture, i.e., mixture of blood an infusate, hematocrit, e.g.,downstream of the exit location.

The controller may be adapted to calculate at least one of a dilution ofthe blood and an admixture hematocrit, e.g., downstream the exitlocation, using a base whole body hematocrit of the patient and adilution of the patient's blood.

The controller may be adapted to calculate at least one of a dilution ofthe blood and an admixture hematocrit, downstream the exit locationusing, the equation (Hct)*(1−dF), wherein Hct is a base whole bodyhematocrit of the patient, dF is the dilution of the blood and isrepresent by the following equation dF=(infusion rate)/(infusionrate+X), and X is an amount of blood per unit time at the core bodytemperature in the blood and infusate mixture, and may be represented bythe equation X=(infusion rate*(T₁−T₂)/(T₄−T₁)), e.g., when there is noreflux, wherein T₁ is a temperature of the blood and infusate mixturedownstream the exit location, T₂ is a temperature of the infusate at oradjacent the exit location, T₃ is temperature adjacent to and upstreamthe exit location, and T₄ is the core body temperature of the patient.

The controller may also be configured to (i) accept as input from aclinician the whole body Hct of the patient at the beginning of thecooling procedure, and (ii) to account for Hct dilution throughout thecooling procedure so as to assure accurate admixture Hct calculation.The controller may account for Hct dilution by taking into account thevolume of infusate added to the patient's blood and the volume of theinfusion fluid output by the patient, e.g., through urination.

The controller may be configured to adjust the Hct according to acomputerized function such as that disclosed in M. A. Neimark, A. A.Konstas, A. F. Laine, J. Pile-Spellman, “Integration of jugular venousreturn and circle of willis in a theoretical human model of selectivebrain cooling,” J. Appl. Physiol., 103: 1848-1856, 2007 (first publishedAug. 30, 2007), equation 6 on page 4, which references A. A. Konstas, M.A. Neimark, A. F. Laine, J. Pile-Spellman, “A theoretical model ofselective cooling using intracarotid cold saline infusion in the humanbrain,” J. Appl. Physiol., 102: 1329-1340, 2007 (first published Dec.14, 2006), equation 6 page 3. Both of these articles are hereinincorporated in their entireties by reference thereto.

The temperature sensors may include a first temperature sensorpositioned downstream relative to an infusate exit location of thecatheter and adapted to measure a temperature of an infusate and bloodmixture when the catheter is placed in a blood vessel of a patient forinfusion of the infusate, a second temperature sensor adapted to measurea temperature of the infusate at or adjacent the exit location, a thirdtemperature sensor adapted to measure a temperature outside the catheterupstream and adjacent the exit location, and a fourth temperature sensoradapted to measure a core body temperature of the patient.

The device may further include a heat exchanger or an infusate pump. Thecontroller may be adapted to receive signals from the temperaturesensors and to control the heat exchanger and/or the pump in accordancewith the signals from the plurality of temperature sensors.

The controller may be adapted to calculate at least one parameter, e.g.,a temperature, of the infusate at or adjacent the exit location.

The controller may be adapted to calculate the temperature of theinfusate at least one of at and adjacent the exit location using atleast one of (a) the temperature of the infusate outside the patient,(b) the infusion rate of the infusate through the insertion device, and(c) a property, e.g., a surface area and/or a thermal conductivity, ofthe insertion device.

The device may include a source of first infusate and a source of secondinfusate. The catheter may be in fluid communication with the source ofthe first infusate and in fluid communication with the source of thesecond infusate. The controller may be adapted to control thetemperature of the infusate by control of a relative proportion of thefirst infusate and second infusate passing through the catheter.

The device may include at least one pump controlled by the controllerand adapted to provide the first infusate from the source of firstinfusate and the second infusate from the source of second infusatethrough the catheter.

The device may include a first heat exchanger controlled by thecontroller and adapted to control the temperature of the first infusateand a second heat exchanger controlled by the controller and adapted tocontrol the temperature of the second infusate.

The controller may be adapted to control the at least one of (a) thetemperature of the infusate, (b) the infusion rate of the infusatethrough the insertion device, and (c) the volume of the infusate passingthrough the insertion device to cause the blood and infusate mixture toat least one of reach and fall below a predetermined target temperature.

According to an exemplary embodiment of the present invention, a devicemay include an insertion device adapted to fluidicly communicate with asource of an infusate, a plurality of sensors, and a controller. Thecontroller may be adapted to receive signals from the sensors indicativeof at least one parameter of a bodily fluid and to control at least oneof (a) at least one parameter of the infusate, (b) an infusion rate ofthe infusate through the insertion device, and (c) a volume of theinfusate passing through the insertion device, in accordance with thesignals from the sensors. At least one of the sensors may be positioneddownstream relative to an infusate exit location of the insertiondevice. At least another one of the sensors may be adapted to measure atleast one of (a) the at least one parameter of the infusate at oradjacent the exit location, (b) the at least one parameter upstream andadjacent the exit location, and (c) a core body temperature of thepatient.

The controller may be adapted to control at least one parameter of theinfusate corresponding to the at least one parameter of the bodilyfluid.

The controller may be adapted to control at least one parameter of theinfusate which is different than the at least one parameter of thebodily fluid.

The controller may be adapted to control at least one of the (a) the atleast one parameter of the infusate, (b) an infusion rate of theinfusate through the insertion device, and (c) the volume of theinfusate passing through the insertion device to at least one of detectand control the at least one parameter of the bodily fluid for apredetermined period of time.

The controller may be adapted to control at least one of (a) an infusionrate of the infusate through the insertion device and (b) a volume ofinfusate passing through the insertion device in accordance with anadmixture hematocrit, e.g., downstream of the exit location.

According to an exemplary embodiment of the present invention, a devicemay include an insertion device adapted to be inserted into a system andfluidicly communicate with a source of an infusate, a sensor locatedexterior to an internal lumen of the insertion device and proximallyaway from an infusate exit location of the insertion device, and acontroller. The controller may be adapted to receive signals from thesensor indicative of at least one parameter of a system fluid, e.g., abodily fluid such as blood, and to control at least one of (a) at leastone parameter of the infusate, (b) an infusion rate of the infusatethrough the insertion device, and (c) a volume of the infusate passingthrough the insertion device in accordance with the signals from thesensor.

The sensor may be a temperature sensor and the controller may be adaptedto receive signals from the temperature sensor and to control at leastone of (a) a temperature of the infusate, (b) an infusion rate of theinfusate through the insertion device, and (c) a volume of the infusatepassing through the insertion device in accordance with the signals fromthe temperature sensor. The sensor may be located, for example, about0.2 cm to about 5 cm proximal the exit location.

The system may be a patient's vasculature filled with blood and thecontroller may be adapted to calculate a native vessel flow rate (nvFR)in a blood vessel in which the insertion device may be inserted.

The system may be adapted to monitor the nvFR, e.g., monitor a plateauin the value of the native vessel flow rate.

The controller may be adapted to at least one of stop, maintain, reduce,and increase infusion of the infusate into the patient based on thenvFR. For example, the controller may increase the flow or decrease thetemperature of the cooled infusate if the rate of change of nvFR remainsbelow a predetermined value.

The controller may also be adapted to at least one of stop, maintain,and reduce infusion of the infusate into the patient upon detection ofthe plateau in the value of the native vessel flow rate.

According to an exemplary embodiment of the present invention, a devicemay include an insertion device adapted to fluidicly communicate with asource of an infusate, and a controller. The controller may be adaptedto control at least one of (a) an infusion rate of the infusate throughthe insertion device into a patient and (b) a volume of infusate passingthrough the insertion device in accordance with an admixture hematocrit,e.g., downstream of an infusate exit location of the insertion device inthe patient.

The device may include a calculation device adapted to calculate anadmixture hematocrit, e.g., downstream of the infusate exit location,based on a measurement of a base whole body hematocrit.

The device may include a calculation device adapted to calculate anadmixture hematocrit, e.g., upstream of the infusate exit location,based on a measurement of a base whole body hematocrit.

The controller may be configured to calculate the admixture hematocritat least one of (a) upstream and (b) downstream of the infusate exitlocation.

The device may include a temperature sensor positioned downstreamrelative to the infusate exit location and adapted to measure atemperature of an infusate and blood mixture when the insertion deviceis placed in a blood vessel of a patient for infusion of the infusate.The controller may be adapted to receive a signal from the temperaturesensor and to calculate the admixture hematocrit, e.g., downstream ofthe infusate exit location, in accordance with the signals from thetemperature sensor.

The controller may be adapted to control at least one of (a) atemperature of the infusate, (b) an infusion rate of the infusatethrough the insertion device, and (c) a volume of the infusate passingthrough the insertion device, in accordance with the signal from thetemperature sensor.

In another embodiment of the invention, a wire for use in anintravascular system, may include a longitudinally extending wire memberand at least one temperature sensor. The wire member may have a distalend, a proximal end, and an outer surface and having at least onetemperature sensor arranged on said outer surface. The at least onetemperature sensor on the wire may be capable of communicating signalsto a controller that controls an infusion pump. The first temperaturesensor on the wire may be positioned on the distal end of the wire andmay be capable of measuring the temperature of a mixture of cooledinfusate and blood. A second temperature sensor on the wire may bepositioned proximal to the first temperature sensor and may be capableof measuring the temperature of cooled infusate. A third temperaturesensor on the wire may be positioned proximal to the second temperaturesensor and may be capable of measuring the temperature of any reflux. Anoptional fourth temperature sensor on the wire may be positionedproximal to the third temperature sensor and may be capable ofdetermining a patient's core temperature.

According to an exemplary embodiment of the present invention, a devicemay include: i) an elongate sensor support device adapted to be insertedinto a patient and having one or more sensors connected to it along itslength; and ii) a controller adapted to receive signals from the sensorsand control at least one of (a) at least one parameter of an infusateinfused into the patient through an insertion device in a downstreamdirection, (b) an infusion rate of the infusate, and (c) a volume of theinfusate, in accordance with at least one parameter of a blood andinfusate mixture downstream relative to an infusate exit location of theinsertion device while the insertion device is placed in a blood vesselof a patient with a downstream flow of blood for infusion of theinfusate, and in accordance with at least one of (a) at least oneparameter of the infusate at least one of at and adjacent the exitlocation, (b) at least one parameter of the infusate upstream andadjacent the exit location, and (c) a core body temperature of thepatient.

The controller may be adapted to control a temperature of the infusatein accordance with (1) a temperature of a blood and infusate mixturedownstream relative to the infusate exit location of the insertiondevice, and (2) at least one of (a) the temperature of the infusate atleast one of at and adjacent the exit location, (b) the temperature ofthe infusate upstream and adjacent the exit location, and (c) a corebody temperature of the patient.

According to an exemplary embodiment of the present invention, a devicemay include: i) an elongate sensor support device adapted to be insertedinto a patient and having one or more sensors connected to it along itslength; and ii) a controller adapted to receive signals from the sensorsand control at least one of (a) at least one parameter of an infusateinfused into the patient through an insertion device in a downstreamdirection, (b) an infusion rate of the infusate, and (c) a volume of theinfusate, in accordance with at least one parameter of a blood andinfusate mixture upstream and adjacent an infusate exit location on theinsertion device.

The sensors may be temperature sensors and the controller may be adaptedto receive temperature signals from the sensors and control at least oneof (a) a temperature of the infusate infused into the patient throughthe insertion device in a downstream direction, (b) an infusion rate ofthe infusate, and (c) a volume of the infusate, in accordance with atemperature of the blood and infusate mixture upstream and adjacent aninfusate exit location on the insertion device.

The controller may be adapted to control a temperature of the infusatein accordance with (1) a temperature of a blood and infusate mixturedownstream relative to the infusate exit location of the insertiondevice, and (2) at least one of (a) the temperature of the infusate atleast one of at and adjacent the exit location, (b) the temperature ofthe infusate upstream and adjacent the exit location, and (c) a corebody temperature of the patient.

According to an exemplary embodiment of the present invention, anintravascular cooling catheter system may include a catheter having atleast one temperature sensor or thermistor, at least one infusatereservoir or source, an infusion pump, and a controller orservomechanism. The catheter may include a longitudinal tubular memberhaving a distal end, a proximal end, and at least one longitudinallyextending lumen, and at least one temperature sensor or thermistorpositioned on the outer surface of the catheter or within a lumenadjacent to or proximal to its distal end. Each temperature sensor maybe electrically or functionally connected to the controller, which mayalso be electrically or functionally connected to the infusion pump. Theoutlet of the infusion pump may be in fluid communication with at leastone lumen of the catheter.

A wire from each temperature sensor may extend through a lumen of thecatheter and/or through the wall of the catheter.

A temperature sensor may be positioned to measure a patient's coretemperature.

In another embodiment of the invention, the distal end of the cathetermay be configured so that blood mixes with cooled infusate.

In another embodiment of the invention, a temperature sensor may bepositioned distal to the distal end of the catheter to measure thetemperature of a mixture of cooled infusate and blood (admixturetemperature).

In another embodiment of the invention, the second temperature sensormay be positioned within a lumen of the catheter.

In another embodiment of the invention, one or more of the temperaturesensors may be annular in shape.

In another embodiment of the invention, the organ cooled may be thebrain.

In an intravascular cooling catheter system, an alarm may sound if thetemperature of the mixture of infusate and blood reaches a targettemperature, if reflux is detected, if the infusion rate of the infusatefalls to zero, if the infusion rate of the infusate exceeds apredetermined maxima, and/or if the admixture hematocrit drops below apredetermined minima.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a patientthrough an insertion device; b) at least one of measuring andcalculating at least one parameter of a bodily fluid; and c) controllingat least one of (i) at least one parameter of the infusate, (ii) aninfusion rate of the infusate through the insertion device, and (iii) avolume of the infusate passing through the insertion device, inaccordance with at least one parameter of a blood and infusate mixture,downstream relative to an infusate exit location of the insertion devicewhen the insertion device is placed in a blood vessel of the patient forinfusion of the infusate, and in accordance with at least one of (a) theat least one parameter of the infusate at or adjacent the exit location,(b) the at least one parameter outside the insertion device upstream andadjacent the exit location, and (c) a core body temperature of thepatient.

The method may include iteratively comparing the at least one parameterof the blood and infusate mixture downstream relative to the exitlocation to a target at least one parameter and decreasing at least oneof the volume and infusion rate of infusate through the insertion deviceif the at least one parameter of the blood and infusate mixturedownstream relative to the exit location falls below the target at leastone parameter and increasing at least one of the volume and infusionrate of the infusate through the insertion device if the at least oneparameter of the blood and infusate mixture downstream relative to theexit location is above the target at least one parameter.

The method may include iteratively comparing the at least one parameterupstream and adjacent the exit location to a predetermined minimum atleast one parameter and reducing at least one of the volume and infusionrate of the infusate through the insertion device if the at least oneparameter upstream and adjacent the exit location falls below thepredetermined minimum at least one parameter.

The method may include iteratively comparing the at least one parameterof the blood and infusate mixture downstream relative to the exitlocation to a target at least one parameter and decreasing at least oneof the volume and infusion rate of infusate through the insertion deviceif the at least one parameter of the blood and infusate mixturedownstream relative to the exit location exceeds the target at least oneparameter and increasing at least one of the volume and infusion rate ofthe infusate through the insertion device if the at least one parameterof the blood and infusate mixture downstream relative to the exitlocation falls below the target at least one parameter.

The method may include iteratively comparing the at least one parameterupstream and adjacent the exit location to a predetermined maximum atleast one parameter and reducing at least one of the volume and infusionrate of the infusate through the insertion device if the at least oneparameter upstream and adjacent the exit location exceeds thepredetermined maximum at least one parameter.

Controlling at least one of (i) at least one parameter of the infusate,(ii) an infusion rate of the infusate through the insertion device, and(iii) a volume of the infusate passing through the insertion device, mayinclude controlling at least one of (i) a temperature of the infusate,(ii) an infusion rate of the infusate through the insertion device, and(iii) a volume of the infusate passing into the patient, in accordancewith a temperature of a blood and infusate mixture downstream relativeto an infusate exit location of the insertion device when the insertiondevice is placed in a blood vessel of the patient for infusion of theinfusate, and in accordance with at least one of (a) a temperature ofthe infusate at or adjacent the exit location, (b) a temperatureupstream and adjacent the exit location, and (c) a core body temperatureof the patient.

The method may include using temperature sensors to measure at least oneof (a) the temperature of the blood and infusate mixture, (b) thetemperature of the infusate at or adjacent the exit location, (c) thetemperature outside the insertion device upstream and adjacent the exitlocation, and (d) the core body temperature.

The method may include calculating at least one of (a) the temperatureof the infusate at or adjacent the exit location, (b) a dilution of theblood downstream relative to an infusate exit location of the insertiondevice, and (c) an admixture hematocrit, e.g., downstream relative to aninfusate exit location of the insertion device.

The method may include calculating the dilution of the blood and theadmixture hematocrit, e.g., downstream the exit location, using theequation (Hct)*(1−dF), where Hct is a base whole body hematocrit of thepatient, dF is the dilution of the blood and is represented by thefollowing equation dF=(infusion rate)/(infusion rate+X), wherein Xrepresents the amount of blood per unit time at the core bodytemperature in the blood and infusate mixture and, e.g., when there isno reflux, is represented by the equationX=(infusion rate*(T ₁ −T ₂)/(T ₄ −T ₁)),wherein T₁ is a temperature of the blood and infusate mixture downstreamthe exit location, T₂ is a temperature of the infusate at or adjacentthe exit location, T₃ is temperature adjacent to and upstream the exitlocation, and T₄ is the core body temperature of the patient.

The calculation of dilution of the whole body hematocrit may also takeinto account the volume of infusate added to the patient's blood and thevolume of the infusion fluid output by the patient, e.g., throughurination.

The method may include iteratively comparing the temperature of theblood and infusate mixture downstream relative to the exit location to atarget temperature and decreasing at least one of the volume andinfusion rate of infusate through the insertion device if thetemperature of the blood and infusate mixture downstream relative to theexit location falls one of (i) below the target temperature, and (ii)more than a predetermined amount below the target temperature, andincreasing at least one of the volume and infusion rate of the infusatethrough the insertion device if the temperature of the blood andinfusate mixture downstream relative to the exit location is above thetarget temperature.

The method may include iteratively comparing the temperature upstreamand adjacent the exit location to a predetermined minimum temperatureand reducing at least one of the volume and infusion rate of theinfusate through the insertion device if the temperature upstream andadjacent the exit location falls one of (i) below the predeterminedminimum temperature, and (ii) more than a predetermined amount below thepredetermined minimum temperature. The predetermined minimum temperaturemay correspond to the core body temperature.

The at least one of (i) the at least one parameter of the infusate, (ii)the infusion rate of the infusate through the insertion device, and(iii) the volume of the infusate passing through the insertion devicemay be controlled in the controlling step such that the blood andinfusate mixture reaches or falls below a predetermined targettemperature.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a patientthrough an insertion device; b) measuring at least one parameter of abodily fluid; and c) controlling at least one of (i) at least oneparameter of the infusate, (ii) an infusion rate of the infusate throughthe insertion device, and (iii) a volume of the infusate passing intothe patient, in accordance with the at least one parameter upstream andadjacent the exit location. Upstream and adjacent the exit location maybe about 0.2 cm to about 5 cm upstream the exit location.

The method may include iteratively comparing the at least one parameterupstream and adjacent the exit location to a predetermined minimum atleast one parameter and reducing at least one of the volume and infusionrate of the infusate through the insertion device if the at least oneparameter upstream and adjacent the exit location falls below thepredetermined minimum at least one parameter.

The at least one parameter of the bodily fluid may be a temperature ofthe bodily fluid and the controlling step (b) above may includecontrolling at least one of (i) a temperature of the infusate, (ii) aninfusion rate of the infusate through the insertion device, and (iii) avolume of the infusate passing into the patient, in accordance with atemperature outside the insertion device upstream and adjacent the exitlocation. The predetermined minimum at least one parameter maycorrespond to a core body temperature of the patient.

The method may include increasing the infusion rate of the infusateuntil reflux is achieved.

The system may be a patient, the system fluid may be the patient'sblood, and the insertion device may be inserted into a blood vessel ofthe patient, and the method may further include: increasing the infusionrate of the infusate until reflux is achieved, and calculating at leastone of (i) a native vessel flow rate in the blood vessel, (ii) adilution factor of the blood in the blood vessel, (iii) an admixturehematocrit, i.e., a hematocrit of the blood and infusate mixture in theblood vessel, and (iv) a temperature of the blood and infusate mixturein the blood vessel in accordance with a determination as to when refluxoccurs.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a patientthrough an insertion device; and b) controlling at least one of (i) aninfusion rate of the infusate through the insertion device, and (ii) avolume of the infusate passing into the patient in accordance with anadmixture hematocrit, e.g., downstream an infusate exit location on theinsertion device.

The method may include iteratively comparing the admixture hematocrit,e.g., downstream the exit location, to a minimum predeterminedhematocrit and reducing at least one of the volume and infusion rate ofthe infusate through the insertion device if the admixture hematocritfalls below the minimum predetermined hematocrit. The method may furtherinclude calculating the admixture hematocrit using the equation(Hct)*(1−dF), as detailed above.

Some of the example embodiments set forth above are directed to themeasurement and/or calculation of temperature and/or hematocrit and theuse of that temperature and/or hematocrit information to control tissueor organ cooling procedures. It should be appreciated that in otherembodiments and as set forth below other characteristics or propertiesof blood, blood flow, infusate, and/or infusate flow may be measured orsensed to control tissue or organ cooling procedures and/or the deliveryof infusate. These embodiments encompass and/or are applicable tocharacteristics or properties that may be sensed or measured todifferentiate infusate from blood or to otherwise facilitate determiningthe rate of blood flow or infusate flow and/or reflux, including, butnot limited to, endogenous and exogenous tracers, etc. For example,sensors may determine a physiological parameter of the blood andinfusate mixture that is measurable, stable, and may have first passviability, e.g., temperature, pH, oxygen content, salt content, drugcontent, tracer content, etc., so that infusate blood flow, and/orreflux may be determined.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a patientthrough an insertion device inserted in the patient's blood vessel; b)at least one of measuring and calculating the patient's nvFR in theblood vessel; and c) controlling at least one of (i) at least oneparameter of the infusate, (ii) an infusion rate of the infusate throughthe insertion device, and (iii) a volume of the infusate passing throughthe insertion device, in accordance with the patient's nvFR.

The method may include decreasing the temperature of the infusate orincreasing the infusion rate or volume of the infusate if a rate ofchange of the nvFR is below a predetermined value.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a patientthrough an insertion device in a downstream direction; and b)controlling at least one of (i) at least one parameter of the infusate,(ii) an infusion rate of the infusate through the insertion device, and(iii) a volume of the infusate passing through the insertion device, inaccordance with a flow rate of a bodily fluid in the downstreamdirection.

A device according to an exemplary embodiment of the present inventionmay include: i) an insertion device adapted to fluidicly communicatewith a source of an infusate and to be placed in a blood vessel; and ii)a controller adapted to control at least one of (a) a temperature of theinfusate, (b) an infusion rate of the infusate through the insertiondevice into the blood vessel, and (c) a volume of the infusate passingthrough the insertion device in a downstream direction into the bloodvessel, in accordance a native vessel blood flow rate in the bloodvessel.

In an exemplary embodiment of the present invention, the infusate mayinclude Na+ ions at a higher concentration than found in the patient'sblood. Sensors on the wire or infusion device may be configured to senseNa+.

According to an exemplary embodiment of the present invention, adelivery device may include: a) an insertion device adapted to fluidiclycommunicate with a source of an infusate, e.g., a fluid or a gas or anymaterial flowable in the system in a first direction, and inserted intoa system filled with a flowing material, e.g., at least one of a fluidand gas; b) a sensor located exterior to an internal lumen of theinsertion device and a distance away from an infusate exit location ofthe insertion device along a second direction opposite the firstdirection; and c) a controller adapted to receive signals from thesensor indicative of at least one parameter of at least one of theflowing material in the system to control at least one of (i) at leastone parameter of the infusate, (ii) an infusion rate of the infusatethrough the insertion device, and (iii) a volume of the infusate passingthrough the insertion device in accordance with the signals from thesensor.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a systemthrough an insertion device in a first direction, said system having atleast one of a fluid and gas flowing therein in the first direction; b)at least one of measuring and calculating at least one parameter of theat least one of a fluid and gas; and c) controlling at least one of (i)at least one parameter of the infusate, (ii) an infusion rate of theinfusate through the insertion device, and (iii) a volume of theinfusate passing through the insertion device, in accordance with atleast one parameter of a mixture of the infusate and the at least one ofa fluid and gas at a position spaced away from an infusate exit locationof the insertion device along the first direction when the insertiondevice is placed in the system for infusion of the infusate, and inaccordance with at least one of (a) the at least one parameter of theinfusate at the exit location, (b) the at least one parameter outsidethe insertion device adjacent the exit location and spaced a distanceaway from the exit location in a second direction opposite the firstdirection, and (c) an average value of a parameter of the at least oneof a fluid and gas in the system.

According to an exemplary embodiment of the present invention, aninfusion method may include: a) infusing an infusate into a systemthrough an insertion device in a first direction, said system having atleast one of a fluid and gas flowing therein in the first direction; b)at least one of measuring and calculating at least one parameter of theat least one of a fluid and gas; and c) controlling at least one of (i)at least one parameter of the infusate, (ii) an infusion rate of theinfusate through the insertion device, and (iii) a volume of theinfusate passing through the insertion device, in accordance with atleast one parameter of a mixture of the infusate and the at least one ofa fluid and gas at a position spaced away from an infusate exit locationof the insertion device along the first direction when the insertiondevice is placed in the system for infusion of the infusate, and inaccordance with a rate of flow of the at least one of a fluid and gas.

One or more of the temperature sensors described herein may be replacedby, for example, inline gas analyzers, including, but not limited to,(a) an opto-chemical pH detector that changes color in response toambient pH readings, (b) an opto-chemical PCO₂ sensor that changes colorin response to the PCO₂, or (c) a Clark oxygen electrode (such as thosebelieved to be available from companies such as Biomedical Sensors,Ltd.). Sensors may detect methylene blue or neuroprotective agents aswell. Modifications of the algorithms discussed below may allow thesetracers to be used to obtain a similar result. The concept, method, andalgorithm would be congruent in embodiments using tracers other thantemperature.

Delivery systems may be applied to deliver agents such aschemotherapeutic agents, where the extraction fraction is so great thatit is desired to administer such agents in as dilute a form as possible,e.g., admixed with a large proportion of physiologically acceptablesolution. The tracer may be administered in the infusate, and thedilution factor, discussed below, may be monitored.

In an exemplary embodiment, the insertion device may include a Dopplerultrasound device, e.g., as disclosed by U.S. Pat. No. 7,211,045, hereinincorporated in its entirety by reference thereto. The Dopplerultrasound device may be adapted to measure the nvFR and/or theadmixture flow rate when the insertion device is placed in the patient'sblood vessel. Doppler measurements may also be taken to determine therelative flow adjacent the distal portion of a catheter to indicate thereflux of infusate/blood admixture.

Alternatively, if it is assumed that the temperature of the infusate andthe core temperature are known, that the temperature is a weighted mean,and the target temperature is the temperature of the admixture, the meanvelocity is used as a measure of change in flow. Thus, assumptions aremade, and reflux is perceived proportional to a change in velocity.

An aspect hereof is to adjust the infusion rate to reach an equilibriumstate so that the blood and infusate mixture reaches or falls below atarget temperature.

Example embodiments of the present invention are described in moredetail below with reference to the appended Figures. The foregoingdescription and examples have been set forth merely as illustrative andare not intended as being limiting. Each of the disclosed aspects andembodiments may be considered individually or in combination with otheraspects, embodiments, and variations thereof. The steps of the methodsdescribed herein are not confined to any particular order ofperformance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic representation of a cooling system according toan exemplary embodiment of the present invention;

FIG. 1B is a cross-sectional view along the line 1B-1B in FIG. 1A;

FIG. 2 is a schematic representation of a cooling system according to anexemplary embodiment of the present invention;

FIG. 3A is a schematic representation of a catheter according to anexemplary embodiment of the present invention positioned in a patient'scarotid artery;

FIG. 3B is a schematic representation of the catheter illustrated inFIG. 3A infusing an infusate into the patient's carotid artery;

FIG. 3C is a schematic representation of the catheter illustrated inFIG. 3A infusing an infusate into the patient's carotid artery, thepatient's free flow contribution reduced compared to that in FIG. 3B;

FIG. 3D is a schematic representation of the catheter illustrated inFIG. 3A surrounded by a reflux of blood and infusate;

FIG. 4A is a schematic representation of a catheter according to anexemplary embodiment of the present invention positioned in a patient'sfemoral artery;

FIG. 4B is a schematic representation of the catheter of FIG. 4A with atip of the catheter exposed to reflux of the blood and infusate;

FIG. 5A is a schematic representation of a catheter according to anexemplary embodiment of the present invention positioned in a patient'scarotid artery;

FIG. 5B is a schematic representation of the catheter illustrated inFIG. 5A infusing an infusate into the patient's carotid artery;

FIG. 5C is a schematic representation of the catheter illustrated inFIG. 5A surrounded by a reflux of blood and infusate;

FIG. 6 is a longitudinal cross-sectional view of an insulated catheteraccording to an exemplary embodiment of the present invention;

FIG. 7 is a transverse cross-sectional view of the insulated catheter ofFIG. 6 along line 7-7 in FIG. 6;

FIG. 8 is a schematic representation of a catheter according townexemplary embodiment of the present invention inserted into a bloodvessel of a patient;

FIG. 9 is a schematic representation of a catheter according to anexemplary embodiment of the present invention;

FIG. 10 is a schematic representation of a catheter according to anexemplary embodiment of the present invention;

FIG. 11 illustrates an exemplary method for the controller systemaccording to the present invention; and

FIG. 12 is a schematic representation of an exemplary embodiment of thecontrol panel according to the present invention.

DETAILED DESCRIPTION

FIG. 1A is a schematic representation of a catheter 2 according to anexemplary embodiment of the present invention including a longitudinallyextending tubular member 4 having a distal catheter section 6 and aproximal catheter section 8. The catheter 2 is inserted into a patientdistal catheter section 6 first. Distal catheter section 6 has one ormore sensors 10 a, 10 b, 10 c, 10 d, such as temperature sensors, e.g.,thermistors, affixed to or embedded in the outer surface 12 and/or innersurface 20 of tubular member 4. Each sensor 10 a, 10 b, 10 c, 10 d mayhave a proximally extending wire 14 that extends into and through alumen 38 of catheter 2 and connects through plug 16 in a manifold 18 toa microprocessor, servomechanism, or controller 22. Alternatively, eachwire 14 may extend through a wall of the catheter 2 or sensors 10 a, 10b, 10 c, 10 d may be wireless. FIG. 1b is a cross-sectional view ofcatheter 2 taken along the line 1B-1B. Controller 22 is able to adjustinfusion rate, e.g., with a tolerance of e.g., about 1 cc/min., tomaintain the measured temperature at the distal catheter tip 23 via,e.g., sensor 10 a, from, e.g., about −10° to about 40° C., for apredetermined period of time. For safety reasons, the length of thepredetermined period of time may be controlled, e.g., so as to so as toprevent a predetermined body temperature drop, e.g., of 1 to 1.5 degreesCelcius, and/or so as to prevent a predetermined whole body hematocritdrop, e.g., to below 25, and/or so as to prevent against a fluidoverload in the patient.

Catheter distal section 6 includes an infusate exit region or area 40,including, for example, outlets, slits, and/or perforations (hereinafter“the outlets”) to facilitate the admixture of infusate with blood. Theoutlets may be designed to generate turbulent flow of the infusate,which further facilitates the admixture of infusate with blood, withoutsignificantly increasing the risk of vascular damage. The design of theoutlets assures that the cooled infusate and blood are totally mixed bythe time the admixture flows past sensor 10 a in FIG. 1. For example,the outlets may have a spiral or screw-like pattern. Further, theoutlets may be oriented perpendicular to a longitudinal axis of thecatheter 2 and the direction of nvFR such as, but not limited to, ninetydegrees plus or minus 25 degrees in relation to the longitudinal axis.Also, a grid or screen in the inlet with many fine holes or a largernumber of smaller orifices in the catheter distal section 6 may be usedto break up laminar flow so as to increase turbulence and mixing.

An infusion pump 24 is operatively connected to controller 22, forexample, through one or more wires 26. Any infusate pump, for example, ablood pump with a wide dynamic range, e.g., from about 2 cc/min to about360 cc/min may be used for pump 24. Cooled infusate in a heat exchanger,such as a temperature controlled reservoir or cooler 30, is drawn intopump 24 through inlet 32 and expelled through outlet 34 in the directionof arrows 36 to the at least one lumen 38 in catheter 2, for example, ata rate of 30 mL/min and a temperature of 0° C. (273K). The temperatureof the infusate is controlled by the controller 22 by adjusting thetemperature in the cooler 30. Alternatively, the temperature of theinfusate infused into a patient may be controlled by using both a heatedsource of infusate, heated by a heat exchanger, such as heater 31, incombination with the cooled source provided by the cooler 30, asillustrated in FIG. 2.

As illustrated in FIG. 2, heater 31, controlled by pump 24 a, is used incombination with cooler 30, controlled by pump 24 b, to determine theultimate temperature of the infusate infused into the patient.Controller 22 determines the relative proportion of infusate pumped fromthe cooler 30 and the infusate pumped from the heater 31. Alternatively,pumps 24 a, 24 b may be replaced with two pressurized reservoirsincluding infusate, for example, at different temperatures andcontroller 22 may control a parameter of the infusate, e.g., itstemperature, by selectively opening up the reservoirs, for example,using valves, to different degrees.

Sensors 10 a, 10 b, 10 c, 10 d are embedded in catheter 2 or affixed tocatheter outer surface 12 or catheter inner surface 20 by anyphysiologically acceptable adhesive or by a physical affixation such asa wire or strap. Sensors 10 a, 10 b, 10 c, 10 d measure a physiologicalparameter that is measurable, and stable, e.g., temperature, pH, oxygencontent, salts, drugs, and some tracers. The iterations of the exemplarydevice and method discussed below use, as an example, temperaturesensors, however, congruent calculations, algorithms, and designcharacteristics may be used with any other of the above-mentionedparameters with only slight modification. Further, while the exemplarydevice discussed below may control the temperature of the infusate,other parameters of the infusate, e.g., temperature, pH, oxygen content,salt content, drug content, tracer content, etc., may be controlled inaccordance with the measured parameter of the blood and infusatemixture. In other words, the measured parameter of the bodily fluid doesnot necessarily correspond to the parameter of the infusate controlledby the controller 22.

Sensor 10 a measures a parameter, such as temperature (T₁), of the bloodand infusate mixture downstream or distal the exit region 40. Sensor 10a may be placed far enough away from the exit region 40, e.g., adistance of about 1 to 10 cm or about ten times the diameter of theblood vessel in which the catheter 2 is positioned, so as to assure thatthe measurement being taken is of a fully mixed blood and infusateadmixture. Sensor 10 b measures a parameter, such as the temperature(T₂), of the cooled infusate at or adjacent the exit region 40 of theinfusate from the catheter 2. Sensor 10 c measures a parameter, such asthe temperature (T₃), at a position adjacent to and upstream, e.g.,about 0.2 cm to about 5 cm, from the exit region 40. As detailed below,sensor 10 c is positioned close enough to the exit region 40 to detectreflux of the infusate. Sensor 10 d measures a parameter, such astemperature (T₄), at a proximal position along the catheter 2. Sensor 10d may be positioned proximal enough along the catheter 2 to assure, forexample, that a core body temperature of the patient is being measured.

Sensors 10 a, 10 b, 10 c, 10 d may each include multiple sensors, forexample, deployed annularly to detect an annular space around catheter2. Each of temperatures T₁ to T₄ may be measured by two or more sensors,in which case an average value for a particular temperature may bedetermined or measured by averaging the measurements from each of thesesensors. The number of sensors used and the number of temperature pointsmeasured may depend upon factors such as the particular applicationand/or the desired functionality. While four temperature points T₁ to T₄are mentioned above, temperatures may be measured at more or lesspoints. Combinations of two or three of T₁ to T₄ may be measured,dependent upon the particular application and/or the desiredfunctionality. Only a single temperature point, such as T₁ or T₃, may beused for certain applications. Further, as detailed below, rather thanor in addition to measuring temperature or other parameters at variouspoints along the catheter, the controller 22 may calculate or estimatethese values.

Sensor 10 a, 10 b, 10 c, 10 d may measure a parameter in addition to orother than temperature. For example, sensors 10 a, 10 b, 10 c, 10 d maymeasure pressure and may include a transducer or diaphragm, optionallywith a fiber optic cable. For representative examples of pressure and/ortemperature sensor technology, see, for example, U.S. Pat. Nos.4,487,206, 4,641,654, 5,427,114, 5,456,251, 5,325,865, 5,647,847,5,866,821, and 5,899,927, each of which is expressly incorporated hereinin its entirety by reference thereto. In addition to measuring backflowof infusate, pressure measurement may be of interest in and of itself.Flow and pressure greater than the desired range may lead to braininjury, and flow and pressure less than the desired range may beinsufficient to achieve organ cooling.

Different systems may have different numbers of sensors, in terms ofplacement and function. A single sensor or multiple sensors can be usedin place of an annular sensor. Only a single sensor at only one of thelocations described herein may be used. Also, the particular type ornumber of sensors is not critical. A patient's core temperature can bemeasured as described above, or it could be measured elsewhere in apatient's body or even calculated as a constant reference point. Thetemperature sensors can be capable of sensing temperatures, for example,in the range of from about 0° to about 50° C.

The information from the sensors 10 a, 10 b, 10 c, 10 d is transmittedto controller 22, which may send signals to pumps 24, 24 a, and 24 b toadjust flow and temperature of infusate according to a control scheme.For example, controller 22 can employ a feedback loop so as toiteratively measure at a predetermined rate a parameter, such as thetemperature (T₁), of the infusate and blood mixture downstream of theexit region 40 and compare it to a predetermined target parameter, forexample, a predetermined target temperature, e.g., 33° C. or 306K. Thecontroller 22 instructs at least one of pumps 24, 24 a, 24 b to continueto increase at least one of a infusion rate and volume of infusatedelivered to the patient and/or instruct cooler 30 and/or heater 31 tocontinue to decrease a temperature of the infusate until T₁ reaches orfalls below the target temperature. The target temperature may be chosenby a user, e.g., so as to achieve a target degree of hypothermia. Forexample, the target temperature may be set to between 33° C. and 36° C.to achieve a mild hypothermia, to between 29° C. and 32° C. to achieve amoderate hypothermia, or to below 28° C. to achieve severe hypothermia.

Controller 22 can also employ a feedback loop so as to iterativelymeasure a parameter, such as the temperature, of either the blood orblood and infusate mixture using sensor 10 c. Controller 22 isprogrammed to look for a change in the parameter detected by sensor 10c, which is reflective of a reflux condition, and upon detection ofreflux instruct the pump 24 to decrease the infusion rate and/or volumeof infusate delivered to the patient.

Controller 22 can also employ a feedback loop so as to iterativelymeasure a patient's nvFR. Controller 22 may be programmed to increase ordecrease flow of infusate or the temperature of the infusate based onthe nvFR, e.g., depending on a rate of change of the nvFR. For example,if the nvFR is not decreasing at a fast enough rate the controller 22may be programmed to increase the flow rate of cooled infusate ordecrease the temperature of the infusate.

The above discussion regarding the use of sensors 10 a, 10 b, 10 c, 10 dassumes that catheter 2 is positioned in a blood vessel in the directionof blood flow. However, catheter 2 can also be positioned in a bloodvessel in a direction opposite the direction of blood flow. In whichcase, the roles of sensors 10 a and 10 c can be switched, i.e., sensor10 a can be used to detect reflux and sensor 10 c can be used to detecta temperature of the infusate and blood mixture.

As the temperature of tissue or an organ in a patient falls, thepatient's metabolism also falls, and this fall in metabolism decreasesblood flow. Metabolism in a human patient substantially ceases in apatient when the temperature of the patient, or at least a particularportion of the patient, approaches 20° C. With regard to the brain,blood flow through a carotid artery is approximately 5 cc/sec (or 300cc/min) when the temperature of the brain is 38° C. However, the rate ofblood flow through the carotid artery quickly falls to near zero as thetemperature of the brain reaches 20° C. Once the temperature of thebrain reaches 20° C. due to the cooled infusate, the volume of cooledinfusate needed to cool the brain also is reduced to near zero. Theblood can be cooled to below 20° C. so as to stop all blood flow throughthe carotid artery. In a situation where the brain is infused withcooled infusate to cool the brain, cooled infusate will be refluxed backalong the infusate catheter as the rate of flow of infusate exceeds theflow necessary for cooling. Reflux can start even before the bloodreaches 20° C. As indicated above, sensor 10 o is positioned on catheter2 so as to detect such a reflux condition.

Reflux of the infusate and blood mixture is illustrated in FIGS. 3A to3D, 4A to 4C, and 5A to 5C. As can be seen in FIGS. 3A to 3D, catheter 2may be positioned in a patient's carotid artery 50. For reference, theleft side of artery 50, as illustrated in FIGS. 3A to 3D, is closer tothe patient's heart. FIG. 3A represents an initial positioning where thepatient's blood is flowing downstream through the carotid artery 50 inthe direction of arrows 52, the temperature of which blood is sensed bysensor 10 d. A cooled infusate travels through catheter 2, exits thecatheter 2 through exit region 40, and enters carotid artery 50, asillustrated in FIG. 3B, and the mixture of blood and infusate 54perfuses downstream toward the patient's brain in the direction of arrow52. Note that for clarity only one of the holes in the exit region 40 ofcatheter 2 is shown in FIG. 1, however, as illustrated in FIGS. 3A to 3Dand 4A to 4C, this region may have multiple holes. Flow to the brainbegins to decrease, as illustrated by the smaller arrow 52 in FIG. 3C,and the infusate and blood mixture 54 eventually refluxes and begins toflow past the exit region 40 in a direction opposite the flow ofinfusate in the catheter 2, e.g., upstream in the carotid artery 50, asreflected by arrow 58 in FIG. 3D. Sensor 10 c senses a temperature offluid flow adjacent the exit region 40. When there is reflux of theinfusate and blood mixture 54, a controller, such as that illustrated inFIG. 1, recognizes this condition by iteratively looking, for example,at a predetermined time interval, for a drop in the temperature measuredby sensor 10 c and sends a signal to a pump, such as that illustrated inFIG. 1, to cause the controller to slow down or stop the infusion ofinfusate. Reflux may be measured during infusion and/or after theinfusion of a bolus of infusate. For example, the infusion may beperformed continuously or non-continuously, e.g., by periodicallyinjecting boluses. For non-continuous infusion, reflux may beperiodically measured after each injection or after a predeterminednumber of injections.

Catheter 2 may also be positioned in a retrograde manner, for example,in the femoral artery 51, as illustrated in FIGS. 4A and 4B. Forreference, the right side of catheter 2 in FIGS. 4A and 4B is closer tothe patient's heart. Infusate, passing through the catheter 2 and exitregion 40, mixes with blood and the mixture 54 flows in the direction ofarrow 52′ away from sensor 10 a and towards sensor 10 c. Flow towardsthe foot begins to slow and the blood and infusate mixture 54 eventuallyrefluxes in the direction of arrow 58′ past sensor 10 a. When there isreflux of the infusate and blood mixture 54, a controller, such as thatillustrated in FIG. 1, recognizes this condition by iteratively looking,for example, at a predetermined time interval, for a drop in thetemperature measured by sensor 10 a and sends a signal to a pump, suchas that illustrated in FIG. 1, to cause the controller to slow down orstop the infusion of infusate.

The controller may be adapted to look to different sensors for differentsignals depending on where the catheter 2 is positioned in the patient.For example, in the situation illustrated in FIGS. 3A to 3D, when thecatheter is positioned in the carotid artery 50 and the direction ofinfusate flow through the catheter 2 is the same as the direction ofblood flow in the carotid artery 50 prior to reflux, the controllerchecks sensor 10 c for a reflux condition, whereas when the catheter 2is positioned in the femoral artery 51, as illustrated in FIGS. 4A and4B, and the flow of infusate through the catheter 2 is opposite that ofthe blood flow in the femoral artery 51 prior to reflux, the controlleris adapted to look to sensor 10 a to detect a reflux condition.Similarly, if the catheter 2 in FIGS. 3A to 3D was inserted retrograde,i.e., flipped 180 degrees such that the exit region 40 was closer to theleft side of the figure, and flow of infusate through the catheter 2 wasin a direction opposite to the direction of blood flow through thecarotid artery 50 before reflux, the controller may be adapted to lookto sensor 10 a to detect a reflux condition. Given that the function ofone or more sensors depends on the positioning of the catheter 2 in thepatient, the controller may accept input from a user indicating adesired mode of controller operation specific to the particular catheterpositioning in the patient's body.

FIGS. 5A to 5C illustrate an exemplary embodiment of an insertion device44, such as a needle or catheter, having a distal opening 46 andtemperature sensors 48 and 49, positioned in a patient's carotid artery50. FIG. 5A represents an initial positioning where the patient's bloodis flowing downstream through the carotid artery 50 in the direction ofarrows 52, the temperature of which blood is sensed by sensor 48. Asillustrated in FIG. 5B, cooled infusate enters carotid artery 50 throughdistal opening 46 and a mixture of infusate and blood 54 perfusesdownstream in the direction of arrow 56 toward the patient's brain.Then, as or after flow to the brain decreases, the infusate and bloodmixture 54 refluxes and begins to flow upstream, as reflected by arrows58 in FIG. 5C. Sensor 49 senses a temperature of fluid flow adjacent toa distal portion 42 of insertion device 44. When there is reflux of theinfusate and blood mixture 54, a controller, such as that illustrated inFIG. 1, recognizes this condition by iteratively looking, for example,at a predetermined time interval, for a drop in the temperature measuredby sensor 49 and sends a signal to a pump, such as that illustrated inFIG. 1, to cause the controller to slow down or stop the infusion ofinfusate.

Given the elongate nature of the catheter 2 used to deliver theinfusate, the infusate can warm up in transit between the pump 24 andthe exit region 40 on the catheter 2. The temperature of the infusateexiting the catheter 2 can be measured using, for example, sensor 10 bor can be calculated by the controller 22 taking into account thiswarming of the infusate.

The temperature of the cold infusate as it exits from the catheter 2 mayalso be calculated using the general thermodynamic equation ΔQ=mc(ΔT) asgenerally discussed on page 927 of “Locally induced hypothermia fortreatment of acute ischemic stroke: a physical feasibility study,”Neuroradiology (2004) 46:923-934, Epub 2004 Nov. 17, herein expresslyincorporated in its entirety by reference thereto, wherein ΔQ representsa change in heat of a given material being measured, m represents themass of the material, c represents the specific heat property of thematerial, and ΔT is the change in temperature of the material.

As detailed below, the general thermodynamic equation ΔQ=mc(ΔT) can beused to solve for the native blood contribution (X), which equation canbe transformed to solve for the temperature of the infusate as it exitsthe catheter.

When the blood and infusate are mixed, the general thermodynamicequation ΔQ=mc(ΔT) becomes:ΔQ _(B) +ΔQ _(I) =m _(B) c _(B) ΔT _(B) +m _(I) c _(I) ΔT _(I)where the subscript B denotes blood and I denotes infusate. Setting theheat capacities of the blood and infusate equal to 1, on the assumptionthat these fluids have heat capacities similar to water, and settingΔQ_(I)=−ΔQ_(B), on the assumption that no heat leaks into the admixturefrom the surrounding tissue, i.e., energy is conserved, the aboveequation can be transformed to 0=ν_(B)ΔT_(B)+ν_(I)ΔT_(I), where ν_(B) isvolume of the blood, T_(A) is the admixture temperature (assuming auniform admixture temperature), ΔT_(B)=T_(A)−T_(B) and represents thechange in blood temperature, and ΔT_(I)=T_(A)−T_(I), which representsthe temperature change in the infusate. Substituting the relevantparameters of, for example, catheter 2 (FIG. 1A) into the equation0=ν_(B)ΔT_(B)+ν_(I)ΔT_(I) including T₁ (temperature of blood andinfusate admixture), T₄ (overall body blood temperature), and T₂(infusate temperature) for T_(A), T_(B), and T_(I), respectively, andreplacing ν_(B) with the native blood contribution (X) multiplied bytime (t) yields the following equation:0=X·t·(T ₄ −T ₁)+IR·t·(T ₁ −T ₂)Solving for native blood contribution (X) and dividing out time (t)yields:

$X = {{IR} \cdot \frac{T_{2} - T_{1}}{T_{1} - T_{4}}}$

The behavior described by the equation above for native blood flowcontribution (X) also applies to other cases in which two fluids possessa property in different amounts and mixing is complete. For example, theinfusate may carry a concentration of sodium ions that differs from thesodium concentration in native blood. Generalizing the sensors in FIG. 1to measure any property P, the concentrations may be defined as:P ₁=[Na⁺] of admixture (meq/L);P ₂=[Na⁺] of infusate (meq/L);P ₃=Reflux [Na⁺](meq/L);P ₄=Overall blood [Na⁺](meq/L);IR=Infusion Rate (cc/s); andX=Native Blood Contribution (cc/s).

The sodium concentration of the admixture (P₁) is the sum of the amountof sodium in the blood and infusate, divided by the total volume of theadmixture. The equation for sodium concentration of the admixture (P₁)is as follows:

$P_{1} = \frac{{P_{2} \cdot {IR} \cdot t} + {P_{4} \cdot X \cdot t}}{{{IR} \cdot t} + {X \cdot t}}$where t is time. Note that the amount of sodium is expressed in the sameform as the amount of heat described above, i.e., as the product ofconcentration, infusion rate and time. Dividing out time and solving forX, the equation above becomes:

$X = {{IR} \cdot \frac{P_{2} - P_{1}}{P_{1} - P_{4}}}$which is a generalized form of the equation

$X = {{IR} \cdot \frac{T_{2} - T_{1}}{T_{1} - T_{4}}}$above.

So as to provide a sufficiently low temperature of the infusate uponexit of the catheter, the catheter can include an insulating sleeve orother coating so as to minimize heat transfer from the blood orsurrounding tissue to the cooled infusate. Further, the catheter can bedelivered into the patient through a guide catheter, in which case theguide catheter itself and an insulator in the guide catheter serve toinsulate the catheter and maintain the temperature of the cooledinfusate.

The catheter can include an insulative annular space 68. FIG. 6illustrates a longitudinal cross section of a distal portion ofinsulated catheter 60. FIG. 7 illustrates a transverse cross section ofcatheter 60 along line 7-7 in FIG. 6. Catheter 60 includes an outercylindrical wall 62 and an inner cylindrical wall 64, which inner wall64 defines a lumen 66 for providing cooled infusate. The insulativeconstruction described may, for example, extend for an entire length orfor only a portion of catheter 60. The annular space 68 can taper todistal section 70 at a distal end of catheter 60. Annular space 68 canbe filled with a biologically safe insulator, including a fluid or gas,such as helium, carbon dioxide, xenon, etc., or other known insulationmaterial such as silica gel, or other materials such as those describedin U.S. Pat. Nos. 2,967,152, 3,007,596, and 3,009,600, each of which isexpressly incorporated herein in its entirety by reference thereto. Theinsulation used should not restrict, or should have only minimal impactupon, the flexibility of catheter 60. The annular space 68 can beinflatable and in fluid communication through an inflation lumen with aninflator. In which case, the catheter 60 is inserted into the patient ina low profile state with the annular space 68 deflated so as tofacilitate insertion and, once positioned, inflated to provideinsulation when cooled infusate is passed through the catheter 60. Uponremoval of the device from the patient, the annular space 68 may beevacuated so as to minimize the profile of the catheter 60.

As indicated above, information from at least one of sensors 10 a, 10 b,10 c, 10 d is transmitted to controller 22, which may in turn sendsignals to pumps 24, 24 a, and/or 24 b, to adjust flow of infusate, andto cooler 30 and/or heater 31, to adjust a temperature of the infusate,according to a control scheme. As part of such a control scheme,controller 22 may also employ a feedback loop so as to iterativelycalculate at a predetermined rate the admixture hematocrit, e.g., thehematocrit of the infusate and blood mixture downstream of the exitregion 40, and compare it to a predetermined minimum hematocrit,required to provide sufficient oxygen delivery to the patient. Thecontroller 22 instructs the pump 24 to decrease at least one of aninfusion rate and volume of the infusate delivered to the patient and/orinstructs the cooler 30 or heater 31 to increase the temperature of theinfusate until the admixture hematocrit rises above a predeterminedminimum, e.g., 25.

The patient's baseline whole body hematocrit may be measured before theprocedure and input by the clinician into the controller 22. During theprocedure the whole body hematocrit will change due to the infusion ofinfusate. Estimates of the patient's whole body hematocrit during theprocedure may be determined by serial whole body measurements orcalculated by the controller 22, for example, using the followingequation:

$\Delta_{HCT} = \frac{p\; V_{RBC}\Delta\; V_{IV}}{V_{IV0}( {V_{IV0} + {p\;\Delta\; V_{IV}}} )}$where V_(RBC) is the total blood cell volume, V_(IVO) is the initialtotal intravascular volume (including V_(RBC)), ΔV_(IV) is the volume ofadded infusate, and p is the fraction of extracellular water that isintravascular. An initial whole body hematocrit of 0.42 and an initialV_(IVO)=5.0 L may be assumed (implying V_(RBC)=2.1 L).

In an exemplary embodiment of the present invention, the hematocrit inthe blood and infusate mixture, i.e., in the admixture hematocrit(amHct), is calculated by controller 22 using data or measurements fromsensors, for example, any of sensors 10 a, 10 b, 10 c, 10 d, and usingthe equation amHct=Hct (1−dF), where dF=IR/(IR+X) and, e.g., when thereis no reflux, X=IR(T₁−T₂)/(T₄−T₁). It should be appreciated that theforegoing equations are merely exemplary. Hct represents the whole bodyhematocrit level of the patient's blood, and dF represents the dilutionfactor, i.e., the percentage of infusate in the mixture of blood andinfusate (when T₃=T₄ and reflux is excluded). IR is the infusion rate atwhich the infusate pump is pumping and X is the free flow contribution,i.e., the flow rate of free or native blood going into the mixture ofblood and infusate.

The controller 22 may be configured to account for Hct dilution bytaking into account the volume of infusate added to the patient's bloodand the volume of the infusion fluid output by the patient, e.g.,through urination. The controller 22 may update the whole bodyhematocrit level of the patient's blood initially input by the clinicianinto the controller 22 at the beginning of the cooling procedure toreflect dilution according to a computerized function.

The function basically monitors the input or amount of fluid that isadded to the patient, i.e., the volume of infused fluid, and monitorsthe output, i.e., urine output. The input may be automaticallycalculated and input by the controller 22 by measuring the amount offluid added, which could be calculated through a number of methodsincluding, but not limited to, subtracting the amount of fluid remainingin the infusate reservoir 30 from the volume of fluid in the reservoir30 at the beginning of the procedure. The output can be automaticallycalculated and input or manually input. One method of calculating thechange of Hct due to the infusion volume is described in M. A. Neimark,A. A. Konstas, A. F. Laine, J. Pile-Spellman, “Integration of jugularvenous return and circle of Willis in a theoretical human model ofselective brain cooling,” J. Appl. Physiol., 103: 1848-1856, 2007 (firstpublished Aug. 30, 2007), equation 6 on page 4, which references A. A.Konstas, M. A. Neimark, A. F. Laine, J. Pile-Spellman, “A theoreticalmodel of selective cooling using intracarotid cold saline infusion inthe human brain,” J. Appl. Physiol., 102: 1329-1340, 2007 (firstpublished Dec. 14, 2006), equation 6 page 3, both of which articles areincorporated herein in their entireties by reference thereto.

Alternatively, a calculation to calculate the whole body Hct dilutionfactor can be performed by assuming that the vast majority of theretained fluid (input−output) will remain intravascular since theintracellular component is small. For example, if we assume that thewhole body blood volume is 5 L, the whole body Hct dilution factor (Z)will equal [(input−output)+5 L]/5 L. Whole body Hct/Z will equaladjusted whole body Hct. The calculation of the adjHct will be aniterative process and be continuously updated.

Controller 22 may employ the algorithm laid out in the flow chart ofFIG. 11. It should be appreciated that alternative algorithms may beemployed, provided that the boundary conditions are met. As used in thechart, T₁ represents the most distal sensor, i.e., the temperature of ablood and infusate mixture and T₂ represents the infusate temperature asit exits the catheter. Further, T₃ is the temperature measured at a“reflux” sensor, for example, about 0.2 to 5 cm proximal to the infusateexit region 40, and T₄ represents the core temperature measured by themost proximal sensor, or otherwise calculated or determined. This lastsensor is placed along the catheter at a position that would accuratelymeasure the core temperature without interference from the reflux or theinfusate. This sensor does not have to be embedded in the catheter. Thistemperature information may be manually programmed from data obtained byother temperature measurement of the patient. Another variable includestT, which is the clinical target temperature that is desired to achievein the target organ or tissue, e.g., selected by the clinician/operatorto be programmed into the controller 22.

As indicated above, T₃ is the temperature measured at a reflux sensor,e.g., about 0.2 to 5 cm proximal to the infusate exit region 40. Itshould be appreciated that a location about 0.2 cm proximal to theinfusate exit region would be used for organs where there is forwardflow of blood during systole and diastole, at all times, whereas alocation about 5 cm proximal to the infusate exit region would be usedfor organs with forward flow only during systole, e.g., the leg.Furthermore, the size of the catheter is also a factor in determiningwhether the location is closer to 0.2 cm proximal to the infusate exitregion or closer to 5 cm proximal to the infusate exit region. In thisregard, it should be appreciated that the larger the catheter is inrelation to the vessel, the greater the possibility and/or extent ofreflux.

In the flow chart of FIG. 11, as reflected in 150, a target temperature(tT) and preset CAH, i.e., a clinically acceptable minimum Hctdelivered, for example, to the organ being treated, are chosen by theoperator and input into the controller 22. The base whole bodyhematocrit level (Hat) of the patient's blood, e.g., as determined byanalysis of a patient's blood specimen, is determined and also inputinto the controller 22. In 152, temperature, information T₁, T₂, T₃, andT₄ are input and the free flow contribution X, the dilution factor dF,and the admixture hematocrit level amHct are calculated by controller22. The T₁, T₂, T₃, and T₄ temperatures, the calculated values X, dF,and amHct, as well as the infusion rate IR can be displayed on a controlpanel for the controller 22, as described below.

In 154, a comparison of the calculated value amHct with a CAH value,i.e., a clinically determined minimum Hct based on routine clinicaldetermination, such as 25, is performed. If amHct is less than the CAHvalue, a signal goes to 156, which causes the controller 22 to reducethe infusion rate of the infusion pump 24 by a preset amount, such as10%. For purposes of this chart, reference to pump 24 applies equally topumps 24 a and 24 b. If amHct is equal to or greater than the CAH value,the T₃ value is compared in 160 with T₄. If T₃ is not less than T₄,i.e., if there is no reflux or a substantial absence of reflux, then T₁is compared in 162 with tT. If T₁ is not less than tT, i.e., the mixtureof blood and infusate has not reached the target temperature, then T₁ iscompared in 164 with tT plus a value such as 0.2°. A determination thatT₁ is not greater than tT plus 0.2° cycles back to 152. However, if itis determined that T₁ is greater than tT plus 0.2°, in 166, the rate ofthe infusion pump 24 is increased by an amount such as 10% until apredetermined maximum infusion pump rate is reached.

When T₄ is determined in 160 to be greater than T₃, i.e., reflux isdetected, or when tT is determined in 162 to be greater than T₁, i.e.,the target temperature of the blood and infusate mixture has beenreached, the rate of the infusion pump IR is reduced by a set percentageor amount, such as 10%, according to the step 168, until IR approachesand/or attains a value of 0. Alternatively, given that the temperatureof the blood and infusate mixture may initially be lower than the organbeing treated, the controller 22 may wait a predetermined period of timeafter T₁ has reached or dropped below tT before reducing the infusionpump rate.

The infusate may also be delivered at a very high rate with the amHct atthe CAH so as to achieve reflux in a short period of time and to coolthe organ being treated, e.g., the brain, as much as possible. In thisscenario, the temperature of the admixture can drop below the targettemperature and the nvFR will slow quickly.

The controller 22 may be programmed to sound alarms or otherwise givefeedback or notice upon certain events or occurrences, such as changesin or reaching a minima or maxima for, for example, core temperature,total fluid administration, fluid rate, or admixture hematocrit level.As indicated in 170 and 172, an alarm may sound if amHct is less thanCAH. As indicated in 174 and 176, an alarm may sound if the infusionpump 24 stops. Further, as indicated in 178 and 180, an alarm may soundif the rate of the infusion pump 24 reaches a preset maximum value.

Controller 22 may also rely on the reflux of the blood and infusateadmixture to calculate the native vessel flow rate (nvFR), dilutionfactor (dF), and admixture Hct. A control algorithm to this effect canbe employed with a device with multiple sensors or with a single sensor,e.g., sensor 10 c (FIG. 1). Controller 22 is programmed to ramp up theflow of infusate until reflux is detected, for example, using sensor 10c, and then decrease the flow of infusate to its normal infusion rate.At an infusion rate at or greater than the nvFR reflux occurs. Thecontroller 22 may then set the native vessel flow rate (nvFR) equal tothe infusion rate when reflux just occurs.

For example, assuming an infusion rate of 5.0 cc in the blood vessel, abase line infusion rate of 0.5 cc may be “ramped up” by, e.g., 0.5 ccevery half second for a total of ten times, until there is reflux. Atthis point in time T3 would be lower than T4 and it would be known thatthe infusion rate in the vessel is greater than 4.5 cc but less than 5.5cc. Additional iterations could be performed by controller 22 to narrowin on the infusion rate over a smaller and smaller range if desired,repeating the above process with smaller infusion doses. The aboveprocess can be reduced to the following general equation:Flow in the vessel=(Infusate initial rate)+((Infusate RateIncrease)/Interval)*(Number of Interval),where the Number of Intervals is equal to the number of intervals whereT3<T4, i.e., when there is reflux of cold infusate.

As can be seen in the equations above, the above determination as toadmixture temperature is made without the use of a sensor downstream ofthe infusate exit region or area 40, e.g., sensor 10 a (FIG. 1). This isuseful because while sensor 10 a provides a temperature reading of theblood and infusate admixture, which may be relied upon as anapproximation of the temperature of the organ being cooled, thetemperatures of the admixture and organ being cooled do not alwayscoincide especially towards the beginning of cooling. The elimination ofthe downstream sensor also reduces the overall cost of the device.

The ramping up of the infusate flow until reflux occurs so as tocalculate nvFR can also be utilized by the controller 22 to accuratelydetermine when the organ being cooled, e.g., the brain, has reached itstarget temperature, at which point the controller 22 reduces or stopsinfusion. The ramping up of the infusate infusion rate and calculationof nvFR may be conducted multiple times, e.g., so as to provide areal-time rapid calculation of nvFR, while the controller 22 monitorsthe value of the nvFR. Upon detecting a predetermined level ofplateauing of the nvFR, i.e., a slope of nvFR over time equal to zero orwithin a predetermined range above or below zero, which indicates thatthe organ being cooled has reached its target temperature, thecontroller 22 may maintain, reduce or stop infusion.

The above determination of target temperature relies on the fact that aplateau in the value of nvFR indicates that the organ being cooled hasreached its target temperature. The blood flow of an organ is related tometabolic rate, which in turn is related to temperature. Using the brainas an example, while infusing a constant flow of cold infusate into theinternal carotid artery, the temperature of the brain begins todecrease, which in turn decreases the metabolic rate, which in turndecreases the nvFR. As the temperature of the brain approaches thetemperature of the cold blood and infusate admixture, it will begin toreach an equilibrium, and thus, the rate of decrease in the temperatureof the brain will slow. The temperature of the brain and the admixturewill eventually reach an equilibrium and be very similar because theinternal carotid artery is an end organ vessel to the brain. At thisequilibrium, the temperature of the brain will plateau or may actuallybegin to increase due to the hemodilution effect of the infusion causingthe metabolic needs to increase. Because the temperature of the brainhas reached a plateau, the metabolic rate and nvFR will also havereached a plateau. As described above, the controller 22 monitors thevalue of nvFR, e.g., to detect this plateau, and maintains, reduces, orstops infusion upon such detection.

As further indicated above, the controller 22 may also be adapted tochange the volume or flow rate of the infusate or the infusatetemperature depending on the nvFR. For example, the controller may beprogrammed to increase the infusate flow rate or decrease itstemperature if the nvFR is not changing fast enough, i.e., the rate ofchange nvFR is below a predetermined minimum.

FIG. 12 is a schematic representation of a control/display panel 184 forthe controller 22, e.g., having a touch sensitive screen. The rate ofthe infusion pump 24 may be shown and controlled at 198. The measured,calculated, or assumed values for T₁ to T₄ may be displayed at 186, 188,190, and 192. The value for tT may be selected and displayed at 194, andthe Hct value may be input and shown at 196. The nvFR may also be shownon the panel 184.

Exemplary items that can be input in the controller 22 at the beginningof the procedure and may or may not be adjusted during the procedure mayinclude (these may have automatic presets already there but may beadjusted):

target temperature of T1;

whole body Hct;

minimum acceptable whole body Hct;

clinical minimum acceptable Admixture Hct;

temperature desired in reservoirs, e.g., pertaining to single coldreservoir system and hot and cold reservoirs in a two reservoir system;

maximum pressure of infusion;

minimum core body temperature;

maximum volume of fluid to be given;

T3 at which Alarm will trigger;

urine output (most likely inputted at a regular interval by an operatoror may be automatic);

Exemplary items to be displayed continuously or triggered (push asbutton to display) may include:

T1 admixture temperature (likely continuous);

T2 infusion temperature at infusion outflow (likely continuous but couldbe triggered);

T4 core body temperature (could be continuous or triggered); admixtureHct (likely continuous);

nvFR and graph of nvFR v. time (likely continuous);

T3 temperature upstream of infusion outflow port (continuouslydisplayed, or more preferably, alarmed based or triggered);

volume administered (likely triggered);

temperature of reservoirs (likely triggered); and

whole body adjusted Hct (likely triggered).

Exemplary alarms may include:

reflux (minimum allowed T3 reached);

minimum core body temperature reached;

minimum acceptable Admixture Hct reached;

maximum pressure of infusion reached;

nvFR plateau reached; and

maximum fluid administered.

For illustrative purposes, in no way intended to be limiting, if thetarget temperature (tT) is set to 33° C. or 306K and the clinicallyacceptable HCT (CAH) for the blood and infusate mixture to set to 25,the baseline whole body hematocrit (hct) is set to 45, and the infusionrate (IR) of the infusate, which can be a normal saline solution, is setto 30 mL/min at 0° C. or 273K, the sensors 10 a, 10 b, 10 c, 10 d may,for example, measure (or controller 22 may calculate) a T₁ temperatureof 308K, a T₂ temperature of 282K, a T₃ temperature of 310K, and a T₄temperature of 310K. The controller 22 then calculates the free flowcontribution asX=IR*(T ₁ −T ₂)/(T ₄ −T ₁)=0.5 mL/sec (308K−282K)/(310K−308K),which yields a free flow contribution of 4 mL/sec. The controller 22also calculates the dilution factor,dF=IR/(IR+X)=0.5 mL/sec/(0.5 mL+4 mL/sec),which yields a dilution factor of 0.11. The controller 22 alsocalculates the hematocrit of the blood and infusate mixture,amHct=Base hct*(1−dF)=45*(1−0.11),which yields a hematocrit of 40.05. Since the amHct is not less thanCAH, T₃ is not less than T₄ (no reflux detected), T₁ is not less thanthe target temperature yet, and T₁ is not greater than the targettemperature plus 0.2, the current infusion rate may be maintained by thecontroller 22. Next, T₁ to T₄ are once again evaluated or measured andthe free flow contribution, dilution factor, and admixture hematocrit isrecalculated. The process may then repeat consistent with thatillustrated in FIG. 11. Alternatively, the infusion rate may bemaintained by the controller 22 for a predetermined period of time andthe infusion rate may be reduced once the period expires irrespective ofwhether the conditions above regarding amHct, T₁, and T₄ are met.

The cooling catheters described and illustrated herein can be used inbrain cooling, where cooled infusate is provided to a patient's brain.However, the catheters may have broader use in cooling other organs,tissue, or limbs, or even in the delivery of substances such aspharmaceuticals or other agents to desired sites within a patient'sbody. The insertion devices and methods described herein may also beused in systems completely independent of the human body and may be usedto influence or control any system parameter or a parameter of anyflowing material in any type of system.

The infusate delivered by the catheter can be saline solution, such as acommercially available saline solution including about 9% sodiumchloride USP, available from, for example, Baxter Healthcare Corporationin Deerfield, Ill. The saline solution can include antioxidants or othervascular agents such as nitric oxide, lidocaine, nitroglycerine,insulin, adenosine, ATP, heat shock proteins, beta blockers, modifiersof calcium channel, modifiers of potassium channel, or other enzymes ormetabolism modifiers, etc., or any type of cardiovascular agent orpreservation solution, e.g., Washington solution. Modifiers ofinflammatory response, modifiers of transmembrane transport, modifiersof lactic acid concentration, or other substances, etc. may also beincluded. The saline solution can also include delta opiod peptides(e.g., D-Ala2-Leu5-enkephalin DADLE) or other hibernation inductiontrigger agents, etc. The infusate can be blood, a blood substitute, or amixture of both.

When the infusate is blood, blood may optionally be removed from thepatient for cooling and then returned to the patient, which may be doneat a single site to minimize trauma to the patient. In a catheter set,an outer catheter extends only partially into a patient's artery, bloodis removed proximally through an annular space between the outercatheter and a distally-extending inner catheter, and cooled blood isreturned through the inner catheter.

Brain cooling can be administered in conjunction with a thrombolyticagent such as TPA, heparin, streptokinase, etc. The thrombolytic agentcan be administered, e.g., according to conventional protocols prior to,during, and/or subsequent to the brain cooling. Similarly, in the eventthat surgical or endovascular intervention is indicated in a strokevictim, brain cooling can be administered in conjunction with such aprocedure.

To effect vascular brain cooling, standard procedures may be followed.For example, first, a guide catheter is established and then the distaltip of a brain cooling catheter is advanced through the femoral artery,through the aorta, e.g., into the internal, or common, carotid artery.Cooled infusate is perfused through one or more lumens in the braincooling catheter to the internal carotid artery.

Similar introduction techniques may be used to access other targetedorgans or tissue. Cooled blood may be provided to one or more coronaryarteries. Hypothermia is believed to be extremely protective of cardiactissue during ischemia and subsequent reperfusion. A catheter, such as acatheter illustrated in FIG. 8, can be advanced through the aorta andthen into the left or right coronary artery. The distal tip of thecatheter may then be positioned in the left or right coronary artery ata point proximal to the occlusion or stenosis. A clinician can determinethe conditions of treatment in terms of tissue target amHCT, blood flow,and duration, which can be similar to those for brain cooling orsupplying cardiac protection during subsequent reperfusion. Infusion canbe used as an adjuvant or as definite therapy during angioplasty,thrombolysis, or chemoembolization or delivery of cardio protectiveagents.

Conventional devices for cooling blood or infusate, for example, duringcardiac procedures, can be used to cool infusate to be infused. Thedevice may be compatible with the temperature ranges hereof and may becapable of being controlled by controller 22. An example of suchavailable equipment is the SARNS TCM water bath available from the SARNSCorp. of Ann Arbor, Mich. Such a water bath is used with acardiopulmonary bypass machine such as the BP40, available fromBiomedicus, Minneapolis, Minn. For details regarding brain coolingprocedures see, for example, A. E. Schwartz et al., “Isolated CerebralHypothermia by Single Carotid Artery perfusion of ExtracorporeallyCooled Blood in Baboons,” Neurosurgery, Vol. 39, No. 3, September 1996,pp. 577-582, and A. E. Schwartz et al., “Selective Cerebral Hypothermiaby Means of Transfemoral Internal Carotid Artery Catheterization,”Radiology, Vol. 201, No. 2, November 1996, pp. 571-572, each of which isexpressly incorporated herein in its entirety by reference thereto.

As illustrated in FIG. 8, a guide catheter 80 is advanced so that adistal end 82 of catheter 80 is positioned in a patient's carotid artery84. Extending from distal end 82 is a microcatheter 86 for delivery ofinfusate. Longitudinally adjacent to microcatheter 86 is a wire 92having one or more sensors 96, 98, 100, and 102, such as temperaturesensors, on its distal section 94. Wire 92 has sensor 96 to measure aparameter of the infusate and blood mixture, sensor 98 to measure aparameter, e.g., the temperature, of the infusate, at a distal end 88 ofmicrocatheter 86, sensor 100 for measuring reflux, and sensor 102positioned to measure a parameter of the patients blood, for example,the patient's core body temperature. It should be appreciated that atracer may be measurable and stable, may be picked up by sensors and mayhave 1st-pass viability (e.g., absorbed completely, excretedcompletely). The arrangement illustrated in FIG. 8 also includes anoptional distal sensor 104 positioned, for example, about 10 to about 25cm distal to sensor 96, which sensor 104 provides additional distalinformation.

Catheter distal end 82 and microcatheter distal end 88 can haveradiopaque markers 106 and 108, respectively, such as rings or annularbands including tantalum, platinum, gold, etc. Sensors 96, 98, 100, 102,and/or 104 can also include radiopaque material. The radiopaque materialfacilitates visualization and positioning of the catheter ends 82 and 88and sensors 96, 98, 100, and 102. For example, marker 108 is justproximal to sensor 98 and marker 106 is well proximal to sensor 102.Other locations of markers and/or sensors are possible. The catheters ormicrocatheters may optionally have anti-thrombotic and/or lubriciouscoatings.

The spacing of the sensors may vary. The spacing between sensors 96 and98 in FIG. 8 may be far enough for sensor 98 to representatively measurethe temperature of the infusate and blood mixture, e.g., from about 1 cmto about 10 cm. However, any spacing between sensors 96 and 98 may beprovided. Sensor 100 will typically measure the temperature of bloodflowing past it. However, the spacing between sensors 98 and 100 may besuch that, when blood flow decreases, sensor 100 will pick up thetemperature of the reflux. This spacing may be, e.g., from about 0.2 cmto about 5 cm. Sensor 102 may be positioned almost any distance proximalto sensor 100 so long as it measures the temperature of free blood flow.These distances are merely illustrative, and it should be appreciatedthat the distances may vary dependent upon factors such as the size ofthe vessel or organ, and/or the application, and/or the materials used,etc.

Wire 92 can include a conventional guidewire construction that ismodified to provide a structure for the sensors. Wire 92 may, forexample, be about 125 cm to about 175 cm in length and have an outerdiameter from about 0.08″ to about 0.38″. The sensors may be glued,welded, or otherwise firmly affixed to wire 92. Wire 92 may be advancedthrough a catheter or sheath or independently into the blood vessel.

As illustrated in FIG. 9, a distal portion 110 of a catheter 112 has asingle lumen 115 including an inner annular sensor 114 used to measure aparameter of the infusate, for example, the temperature of the infusate.Distal portion 110 has perforations 116 so that blood flowing exteriorto catheter 112 mixes with cooled infusate and flow together as aninfusate and blood mixture in the direction of arrow 120. Distal annularsensor 122 is positioned to sense, for example, the temperature of theinfusate and blood mixture, annular sensor 124 is positioned to detectreflux, and proximal annular sensor 126 is positioned to measure, forexample, the body core temperature of the patient.

Sensors 114, 122, 124, and 126 may be spaced relative to each other asdescribed above in connection with FIG. 8. The annular construction ofthe sensors may be facilitated by use of conductive material such asgold that encircles the catheter surface, to which the sensors may beattached. The sensors may be fixed in place, for example, with a film orother arrangement, to minimize any adverse effects of fluid flowingpast.

FIG. 10 illustrates a device that includes a microcatheter 136 connectedto and coextensive with catheter 138 along a portion of catheter 138.The distal end 140 of catheter 138 extends pasta distal end 142 ofmicrocatheter 136, for example, for about 1 to about 20 cm. Annularsensor 144 measures, for example, the patient's core temperature andsensor 146 measures, for example, the reflux temperature. Sensor 148 ispositioned at or slightly distal to the distal end 142 of microcatheter136 to measure, for example, the temperature of the infusate. Sensor 148need not be annular, in which case, it may be positionedcircumferentially directly in front of the microcatheter 136. Mostdistal annular sensor 150 is positioned to measure, for example, thetemperature of the mixture of infusate and blood. Microcatheter 136 canbe a separate catheter bound to catheter 138 and/or laterally embeddedin catheter 138. Microcatheter 136 can also be integrally formed withcatheter 138.

The catheters described above can include conventional bio-compatiblematerials used in the catheter field. For example, the catheters areformed of suitable low-friction bio-compatible polymers such as, forexample, extruded polyethylene, polyvinyl chloride, polystyrene, orpolypropylene or copolymers thereof, etc. The inner elongated tubularmembers may have, for example, an outer diameter from about 3 Fr toabout 9 Fr and an inner diameter from about 0.038″ to about 0.105″. Thecatheter may include a supportive backing, e.g., made from stainlesssteel or ceramic or fiberglass weave. The ceramic backing has the addedbenefit of decreasing the heat loss of the cooled infusate as it flowsthrough the insertion device into the patient.

What is claimed is:
 1. A method comprising: communicating with a sourceof an infusate; controlling at least one of (a) a temperature of theinfusate, (b) an infusion rate of the infusate through an insertiondevice, and (c) a volume of the infusate passing through the insertiondevice in a downstream direction, in accordance with a temperature of ablood and infusate mixture downstream relative to an infusate exitlocation of the insertion device while the insertion device is placed ina blood vessel of a patient with a downstream flow of blood for infusionof the infusate, and in accordance with at least one of (a) atemperature of the infusate at least one of at and adjacent the exitlocation, (b) a temperature upstream and adjacent the exit location, and(c) a core body temperature of the patient; receiving signals from aplurality of temperature sensors, at least one of the temperaturesensors is positioned downstream relative to the infusate exit location;measuring a temperature of the infusate and blood mixture by at leastone of the temperature sensors; and measuring at least one of (a) thetemperature of the infusate adjacent the exit location, (b) thetemperature upstream and adjacent the exit location, and (c) the corebody temperature of the patient by at least another one of thetemperature sensors; wherein the temperature sensors include a firsttemperature sensor positioned downstream relative to an infusate exitlocation of a catheter and adapted to measure the temperature of theinfusate and blood mixture when the catheter is placed in the bloodvessel of the patient for infusion of the infusate, a second temperaturesensor adapted to measure the temperature of the infusate at least oneof at and adjacent the exit location, a third temperature sensor adaptedto measure a temperature outside the catheter upstream and adjacent theexit location, and a fourth temperature sensor adapted to measure thecore body temperature of the patient.
 2. The method according to claim1, further comprising: receiving signals from the temperature sensors;and controlling at least one of a heat exchanger and an infusate pump inaccordance with the signals from the plurality of temperature sensors.3. The method according to claim 1, further comprising calculating atleast one of (a) a dilution of the blood and (b) a hematocrit downstreamthe exit location using the equation (Hct)*(1−dF), wherein Hct is a basewhole body hematocrit of the patient, dF is the dilution of the bloodand is represent by the following equation dF=(infusion rate)/(infusionrate+X), X is an amount of blood per unit time at the core bodytemperature in the blood and infusate mixture and is represented by theequation X=(infusion rate*(T1−T2)/(T4−T1)), T1 is a temperature asmeasured by the first temperature sensor, T2 is a temperature asmeasured by the second temperature sensor, T3 is a temperature asmeasured by the third temperature sensor, and T4 is a temperature asmeasured by the fourth temperature sensor.
 4. The method according toclaim 1, further comprising controlling at least one of (a) the infusionrate of the infusate through the insertion device and (b) a volume ofinfusate passing through the insertion device in accordance with ahematocrit downstream of the exit location.
 5. The method according toclaim 1, further comprising calculating at least one parameter of theinfusate at least one of at and adjacent the exit location.
 6. Themethod according to claim 5, further comprising calculating thetemperature of the infusate at least one of at and adjacent the exitlocation using at least one of (a) the temperature of the infusateoutside the patient, (b) the infusion rate of the infusate through theinsertion device, and (c) at least one of a surface area and thermalconductivity of the insertion device.
 7. The method according to claim1, further comprising accepting as input a base whole body hematocrit ofthe patient (Hct) and to update the Hct based on the volume of infusionfluid passing through the insertion device into the patient and a volumeof fluid output by the patient.
 8. The method according to claim 1,further comprising controlling the at least one of (a) the temperatureof the infusate, (b) the infusion rate of the infusate through theinsertion device, and (c) the volume of the infusate passing through theinsertion device in accordance with a native vessel blood flow rate inthe blood vessel.
 9. A method comprising: communicating with a source ofan infusate; controlling at least one of (a) a temperature of theinfusate, (b) an infusion rate of the infusate through an insertiondevice, and (c) a volume of the infusate passing through the insertiondevice in a downstream direction, in accordance with a temperature of ablood and infusate mixture downstream relative to an infusate exitlocation of the insertion device while the insertion device is placed ina blood vessel of a patient with a downstream flow of blood for infusionof the infusate, and in accordance with at least one of (a) atemperature of the infusate at least one of at and adjacent the exitlocation, (b) a temperature upstream and adjacent the exit location, and(c) a core body temperature of the patient; and calculating at least oneof (a) a dilution of the blood and (b) a hematocrit downstream the exitlocation using a base whole body hematocrit of the patient (Hct) and thedilution of the blood (dF) based on the equation (Hct)*(1−dF), whereindF=(infusion rate)/(infusion rate+X), wherein X is an amount of bloodper unit time at the core body temperature in the blood and infusatemixture and is represented by the equation X=(infusionrate*(T1−T2)/(T4−T1)), T1 is a temperature of the blood and infusatemixture downstream the exit location, T2 is a temperature of theinfusate at least one of at and adjacent the exit location, T3 istemperature adjacent to and upstream the exit location, and T4 is thecore body temperature of the patient.
 10. A method comprising:communicating with a source of an infusate; controlling at least one of(a) a temperature of the infusate, (b) an infusion rate of the infusatethrough an insertion device, and (c) a volume of the infusate passingthrough the insertion device in a downstream direction, in accordancewith a temperature of a blood and infusate mixture downstream relativeto an infusate exit location of the insertion device while the insertiondevice is placed in a blood vessel of a patient with a downstream flowof blood for infusion of the infusate, and in accordance with at leastone of (a) a temperature of the infusate at least one of at and adjacentthe exit location, (b) a temperature upstream and adjacent the exitlocation, and (c) a core body temperature of the patient; controllingflow of infusate from a first pressurized reservoir of infusate at afirst temperature through the insertion device; controlling flow ofinfusate from a second pressurized reservoir of infusate at a secondtemperature through the insertion device; and controlling thetemperature of the infusate flowing through the insertion device viacoordinated control of both the flow of infusate from the firstpressurized reservoir and the flow of infusate from the secondpressurized reservoir.
 11. A method, comprising: communicating with asource of an infusate; receiving signals from a sensor located exteriorto an internal lumen of an insertion device positioned in a systemfilled with at least one of a fluid and gas flowing in a firstdirection, the signals indicative of at least one parameter of at leastone of the fluid and gas to control at least one of (a) at least oneparameter of the infusate, (b) an infusion rate of the infusate throughthe insertion device, and (c) a volume of the infusate passing throughthe insertion device in accordance with the signals from the sensor,wherein the sensor is located a distance away from an infusate exitlocation of the insertion device along a second direction opposite thefirst direction; and detecting reflux and calculating at least one of(i) a native vessel flow rate in a blood vessel in which the insertiondevice is inserted, (ii) a dilution factor of the blood in the bloodvessel, (iii) a hematocrit of a mixture of the blood and infusate in theblood vessel, and (iv) a temperature of the blood and infusate mixturein the blood vessel in accordance with a determination as to when refluxoccurs.
 12. The method according to claim 11, further comprisingincreasing the infusion rate of the infusate until reflux is achieved.13. The method according to claim 11, further comprising: calculating anative vessel flow rate in a blood vessel in which the insertion deviceis inserted; and controlling at least one of a temperature, the volume,and the flow rate of the infusate into the patient based on the nativevessel flow rate.
 14. The method according to claim 11, furthercomprising: communicating with a source of an infusate; receivingsignals from a sensor located exterior to an internal lumen of aninsertion device positioned in a system filled with at least one of afluid and gas flowing in a first direction, the signals indicative of atleast one parameter of at least one of the fluid and gas to control atleast one of (a) at least one parameter of the infusate, (b) an infusionrate of the infusate through the insertion device, and (c) a volume ofthe infusate passing through the insertion device in accordance with thesignals from the sensor, wherein the sensor is located a distance awayfrom an infusate exit location of the insertion device along a seconddirection opposite the first direction; calculating a native vessel flowrate in a blood vessel in which the insertion device is inserted;monitoring a plateauing of the native vessel flow rate; and performingat least one of stop, maintain, and reduce infusion of the infusate intothe patient upon detection of the plateauing of the native vessel flowrate.